Synthetic studies of the lichen macrolide lepranthin. Stereoselective synthesis of the diolide framework based on regioselective epoxide-opening reactions

Article abstract of DOI:10.1248/cpb.59.525

Stereoselective synthesis of the 16-membered diolide 27, a fully functionalized congener of lepranthin (1), is described. The requisite five asymmetric carbon centers in monomer 23 were constructed in a highly stereoselective manner by using different epo

Full text of DOI:10.1248/cpb.59.525

April 2011
Communication to the Editor
Chem. Pharm. Bull. 59(4) 525—527 (2011)
525
Our synthesis started with allyl alcohol 24) which was de-
rived from commercially available methyl (R)-3-hydroxy-
butylate in four steps. First, 2 was converted to a,b-unsatu-
rated g,d-epoxy ester 6 by a four-step reaction sequence: (1)
Katsuki–Sharpless epoxidation5) with L-(ꢀ)-diethyl tartrate
(DET), Ti(OiPr)4, and tert-butyl hydroperoxide (TBHP) in
CH2Cl2 at ꢁ30 °C, leading to epoxy alcohol 3 (87%); (2)
Dess–Martin oxidation6) followed by a Wittig reaction (91%
yield); (3) desilylation (97%); (4) protection of the resulting
alcohol with a MOM group (95%). Reductive cleavage of the
epoxide 6 with HCOOH and tris(dibenzylideneacetone)-di-
palladium(o)-chloroform adduct (Pd2(dba)3·CHCl3)7) smooth-
ly occurred to give alcohol 7 regioselectively in 91% yield,
which was transformed into epoxy alcohol 10 through the se-
quence of protection of the secondary alcohol with a silyl
group, diisobutylaluminum hydride (DIBAH) reduction, and
Synthetic Studies of the Lichen
Macrolide Lepranthin. Stereoselective
Synthesis of the Diolide Framework
Based on Regioselective Epoxide-
Opening Reactions
a
Hisashi TAKADA, Shinji NAGUMO, ,a Eiko YASUI,a
*
b
,a
*
Megumi MIZUKAMI, and Masaaki MIYASHITA
a Department of Applied Chemistry, Kogakuin University; 2665–1
Nakano, Hachioji, Tokyo 192–0015, Japan: and b Hokkaido
Pharmaceutical University, School of Pharmacy; 7–1 Katsuraoka,
Otaru 047–0264, Japan.
Received December 9, 2010; accepted January 14, 2011; published
online January 24, 2011
the Katsuki–Sharpless epoxidation. The substitution reaction
Stereoselective synthesis of the 16-membered diolide 27, a
fully functionalized congener of lepranthin (1), is described. The
requisite five asymmetric carbon centers in monomer 23 were
constructed in a highly stereoselective manner by using different
8—10)
of 10 with Me2CuCNLi2
in Et2O furnished a mixture of
11 and its regioisomer in a ratio of ca. 3 : 1, which was
treated with NaIO4 in aqueous tetrahydrofuran (THF) to
afford the pure 1,3-diol 11 in 62% isolated yield. The diol
11 was then converted to a,b-unsaturated ester 14 in three
steps: (1) selective oxidation of the primary alcohol to alde-
hyde with 2,2,6,6-tetramethyl-1-piperidinyloxy free radical
(TEMPO) (91%)11); (2) Horner–Emmons olefination (84%);
(3) protection of the secondary alcohol with a MOM group
(95%). Reduction of the ester 14 with DIBAH followed by
a,b-unsaturated g,d-epoxy esters
epoxide-opening reactions of
and epoxy alcohol derivatives as the key steps. The monomer 23
was successfully transformed into the MOM protected diolide
27 by Yamaguchi macrolactonization.
Key words lepranthin; regioselective epoxide-opening reaction; Yama-
guchi macrolactonization; dimeric macrolide
the Katsuki–Sharpless epoxidation produced epoxy alcohol
8)
Macrolide antibiotics have provided us with good opportu- 16 in 91% yield. Upon treatment of 16 with Me2CuCNLi2
nities discovering drugs that exhibit a wide range of biologi- in Et2O, the regioselective substitution reaction smoothly oc-
cal activities. Bacteria, fungi and algae produce a large curred to give diol 17 as a single product in 97% yield, which
number of macrolides, which are classified as polyketide was then converted to benzyl ester 20 by a three-step reaction
macrolides in their biosynthetic pathways. Interestingly, a sequence: (1) TEMPO oxidation11); (2) sodium chlorite oxi-
few polyketide macrolides have been isolated from lichens, dation12—15); (3) esterification with benzyl bromide in the
which may represent a symbiotic relationship between fungi presence of Cs2CO3 and TBAI in N,N-dimethylformamide
and algae.1) Lepranthin (1) was isolated from the crustaceous (DMF) (92%, three steps). The resulting secondary alcohol
lichen Arthonia impolita (Ehrh.) BORRER by Zopf in 1904.2) 20 was protected with a MOM group to provide 21 in 97%
Almost a century later, Huneck and colleagues determined yield.
the structure of 1 using NMR techniques and finally X-ray
Thus, the contiguous five asymmetric carbon centers in the
crystallographic analysis, which disclosed the unique 16- monomer counterpart 21 were constructed in a highly stere-
membered dimeric macrolide structure containing two sec- oselective manner by using different epoxide-opening reac-
ondary hydroxyl groups and four secondary acetates.3) In tions of the g,d-epoxy unsaturated ester 6 and two epoxy al-
spite of its characteristic macrolide structure, biological ac- cohols 10 and 16. The remaining task for the synthesis of
tivity and synthetic studies of 1 have not been reported so far. lepranthin (1) is construction of dimeric structure by macro-
We thought that a sufficient supply of 1 by total synthesis lactonization. For this end, when 21 was treated with DDQ in
should advance the study of biological properties and set aqueous THF, the silyl group was successfully removed to
about synthetic studies. We report herein the stereoselective give rise to alcohol 22 in 91% yield.16) On the other hand, hy-
synthesis of methoxymethyl group (MOM) protected diolide drogenolysis of 21 over a Pd/C catalyst in AcOEt provided
27, a fully functionalized congener of lepranthin (1), based carboxylic acid 23, which was immediately subjected to es-
on regioselective epoxide-ring opening strategies and subse- terification with 22 using the Yamaguchi reagent17) in the
quent Yamaguchi macrolactonization.
presence of N,N-diisopropylethylamine (DIPEA) and 4-(di-
methylamino)pyridine (DMAP) leading to dimeric ester 2418)
(78%). The diester 24 was transformed into seco-acid 26 via
the same reaction sequence for 21, that is, removal of the
silyl group with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) followed by removal of the benzyl ester under cat-
alytic hydrogenation. Finally, the seco-acid 26 was trans-
formed into the targeted diolide 2719) by macrolactoniza-
tion17) with 2,4,6-trichlorobenzoyl chloride in the presence of
DIPEA and DMAP in 52% yield.
Fig 1. Lepranthin (1)
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: bt13071@ns.kogakuin.ac.jp

526
Vol. 59, No. 4
Reagents and Conditions: (a) L-(ꢀ)-DET, Ti(OiPr)4, TBHP, CH2Cl2, ꢁ30 °C; (b) Dess–Martin periodinane, CH2Cl2, then
Ph3PꢂCHCO2Me; (c) tert-n-butylammonium fluoride (TBAF), THF; (d) MOMCl, DIPEA, CH2Cl2; (e) Pd2(dba)3·CHCl3, HCOOH,
Et3N, Bu3P; (f) tert-butyldimethylsilyl chloride (TBSCl), imidazole, DMF; (g) DIBAH, THF, ꢁ25 °C; (h) L-(ꢀ)-diisopropyl tartrate
(DIPT), Ti(OiPr)4, TBHP, CH2Cl2, ꢁ40 °C; (i) MeLi, CuCN, Et2O, ꢁ55 °C, then NaIO4, THF, H2O; (j) TEMPO, NaOCl, tetra-n-
butylammonium bromide (TBAB), CH2Cl2, NaHCO3 aq., 0 °C; (k) (MeO)2P(O)CH2CO2Me, NaH, THF, 0 °C; (l) MOMCl, DIPEA,
tetra-n-butylammonium iodide (TBAI), (CH2Cl)2, 50 °C; (m) DIBAH, THF, ꢁ30 °C, (n) L-(ꢀ)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2,
ꢁ40 °C; (o) MeLi, CuCN, Et2O, ꢁ50 to ꢁ10 °C, then NaIO4, THF, H2O; (p) TEMPO, NaOCl, TBAB, CH2Cl2, NaHCO3 aq., 0 °C;
(q) NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, THF, H2O, 0 °C; (r) benzyl bromide (BnBr), Cs2CO3, TBAI, DMF; (s) MOMCl,
DIPEA, TBAI, (CH2Cl)2, 50 °C.
Chart 1
Reagents and Conditions: (a) DDQ, THF, H2O, 60 °C; (b) Pd/C, H2, AcOEt; (c) 22, 2,4,6-trichlorobenzoyl chloride, DIPEA,
DMAP, THF; (d) 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP, THF, benzene.
Chart 2

April 2011
527
Reagents and Conditions: (a) TsOH·H2O, tBuOH, H2O, 80 °C; (b) HCl, THF, 0 °C; (c) CF3SO3H, CH2Cl2, ꢁ20 °C.
Chart 3
9) Johnson M. R., Nakata T., Kishi Y., Tetrahedron Lett., 20, 4343—4346
(1979).
10) Nagaoka H., Kishi Y., Tetrahedron, 37, 3873—3888 (1981).
11) Mico A. D., Margarita R., Parlanti L., Vescovi A., Piancatelli G., J.
Org. Chem., 62, 6974—6977 (1997).
12) Lindgren B. O., Nilsson T., Acta Chem. Scand., 27, 888—890 (1973).
13) Kraus G. A., Taschner M., J. Org. Chem., 45, 1175—1176 (1980).
14) Kraus G. A., Roth B., J. Org. Chem., 45, 4825—4830 (1980).
15) Bal B. S., Childers W. E. Jr., Pinnick H. W., Tetrahedron, 37, 2091—
2096 (1981).
Next, we carried out preliminary experiments for removal
of the MOM groups in 27. However, surprisingly, treatment
t
of 27 with a catalytic amount of TsOH·H2O in BuOH/H2O
at 80 °C or HCl in THF at 0 °C produced a mixture of two
fragment lactones 28 and 29. On the other hand, upon treat-
ment of 27 with CF3SO3H in CH2Cl2 at ꢁ20 °C, symmetric
16-membered diolide 30 containing two dioxane rings was
formed.
In summary, we succeeded in the stereoselective synthesis
of the diolide congener 27 of lepranthin (1) based on regio-
and stereospecific epoxide-opening reactions. Namely, reduc-
tive cleavage of the epoxide 6 with HCOOH and Pd2(dba)3·
CHCl3 was used for construction of the C7 asymmetric cen-
ter. On the other hand, four contiguous asymmetric carbon
centers at the C2—C5 positions were constructed by the
epoxide-opening reactions with the Lipshutz reagent (10→11
and/or 16→17). The subsequent key macrolactonization was
successfully performed using the Yamaguchi reagent. Further
studies toward the total synthesis of lepranthin (1) from the
crucial intermediate 27 is now in progress in our laboratory.
16) Tanemura K., Suzuki T., Horaguchi T., J. Chem. Soc. Perkin Trans. 1,
2997—2998 (1992).
17) Inanaga J., Hirata K., Saeki H., Katsuki T., Yamaguchi M., Bull. Chem.
Soc. Jpn., 52, 1989—1993 (1979).
18) For data of 24: [a]D27 ꢁ25.11 (cꢂ1.02, CHCl3); HR-ESI-MS m/z
1001.5831 (Calcd for C49H90O17Na: 1001.5845); IR (ATR) 1731 cmꢁ1
;
1H-NMR (400 MHz, CDCl3) d: 7.36—7.29 (5H, m), 5.25—5.19 (1H,
br m), 5.12 (2H, s), 4.66—4.54 (12H, m), 4.04 (1H, tt, Jꢂ9.6, 2.8 Hz),
3.86—3.81 (1H, m), 3.80—3.74 (2H, br m), 3.73—3.65 (3H, m), 3.38
(6H, s), 3.36 (3H, s), 3.35 (3H, s), 3.34 (3H, s), 3.32 (3H, s), 2.96 (1H,
qd, Jꢂ6.8, 6.0 Hz), 2.87 (1H, qd, Jꢂ7.2, 5.6 Hz), 2.17—2.11 (2H, m),
1.94—1.53 (7H, m), 1.41—1.33 (1H, m), 1.22—1.18 (12H, m), 0.89
(3H, d, Jꢂ7.2 Hz), 0.89 (9H, s), 0.83 (3H, d, Jꢂ7.2 Hz), 0.09 (3H, s),
0.07 (3H, s); 13C-NMR (100 MHz, CDCl3) d: 174.03 (C), 173.66 (C),
135.88 (C), 128.46 (2C, CH), 128.22 (2C, CH), 128.14 (CH), 98.35
(CH2), 98.13 (CH2), 98.87 (CH2), 95.81 (CH2), 95.73 (CH2), 95.51
(CH2), 83.44 (CH), 83.34 (CH), 74.97 (CH), 74.92 (CH), 71.69 (CH),
70.15 (CH), 69.72 (CH), 67.15 (CH), 66.21 (CH2), 56.04 (2C, CH3),
55.88 (CH3), 55.74 (CH3), 55.40 (CH3), 55.22 (CH3), 45.04 (CH2),
43.07 (2C, CH), 41.65 (CH2), 38.86 (CH2), 38.01 (CH), 37.98 (CH),
35.52 (CH2), 25.92 (3C, CH3), 21.83 (CH3), 21.20 (CH3), 17.99 (C),
12.27 (2C, CH3), 10.94 (CH3), 10.74 (CH3), ꢁ3.80 (CH3), ꢁ4.62
(CH3).
Acknowledgement Financial support from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (a Grant-in-Aid for Scien-
tific Research (B) (No. 19350027) and Advanced Promotion Research Pro-
gram for Education of Graduate School) is gratefully acknowledged.
References and Notes
1) Omura S., “Macrolide Antibiotics,” Academic Press, 2002.
2) Zopf W., Liebigs Ann. Chem., 336, 46—85 (1904).
3) Polborn K., Steglich W., Connolly J. D., Huneck S., Z. Naturforsch. B:
Chem. Sci., 50, 1111—1114 (1995).
19) For data of 27: [a]D30 ꢁ40.87 (cꢂ1.01, CHCl3); HR-ESI-MS m/z
779.4412 (Calcd for C36H68O16Na: 779.4405); IR (ATR) 1728 cmꢁ1
;
4) Garbaccio R. M., Stachel S. J., Baeschlin D. K., Danishefsky S. J., J.
Am. Chem. Soc., 123, 10903—10908 (2001).
5) Katsuki T., Sharpless K. B., J. Am. Chem. Soc., 102, 5974—5976
(1980).
6) Dess D. B., Martin J. C., J. Org. Chem., 48, 4155—4156 (1983).
7) Oshima M., Yamazaki H., Shimizu I., Nisar M., Tsuji J., J. Am. Chem.
Soc., 111, 6280—6287 (1989).
8) Lipshutz B. H., Kozlowski J., Wilhelm R. S., J. Am. Chem. Soc., 104,
2305—2307 (1982).
1H-NMR (400 MHz, CDCl3) d: 5.21 (2H, m), 4.70—4.53 (12H, m),
3.79 (2H, br d, Jꢂ5.6 Hz), 3.75—3.66 (4H, m), 3.40 (6H, s), 3.35 (6H,
s), 3.32 (6H, s), 2.84 (2H, quintet, Jꢂ6.7 Hz), 2.15 (2H, m), 1.96—
1.75 (4H, m), 1.75—1.57 (4H, m), 1.21 (6H, d, Jꢂ6.4 Hz), 1.20 (6H,
d, Jꢂ6.4 Hz), 0.86 (6H, d, Jꢂ6.8 Hz); 13C-NMR (100 MHz, CDCl3) d:
173.77 (C), 98.23 (CH2), 95.76 (CH2), 95.47 (CH2), 82.98 (CH), 74.42
(CH), 70.13 (CH), 70.03 (CH), 56.09 (CH3), 55.92 (CH3), 55.46
(CH3), 43.11 (CH), 41.37 (CH2), 37.58 (CH), 35.06 (CH2), 21.21
(CH3), 12.11 (CH3), 10.67 (CH3).